Results for “fda”
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FDA Allows Pooled Tests and a Call for Prizes

The FDA has announced they will no longer forbid pooled testing:

In order to preserve testing resources, many developers are interested in performing their testing using a technique of “pooling” samples. This technique allows a lab to mix several samples together in a “batch” or pooled sample and then test the pooled sample with a diagnostic test. For example, four samples may be tested together, using only the resources needed for a single test. If the pooled sample is negative, it can be deduced that all patients were negative. If the pooled sample comes back positive, then each sample needs to be tested individually to find out which was positive.

…Today, the FDA is taking another step forward by updating templates for test developers that outline the validation expectations for these testing options to help facilitate the preparation, submission, and authorization under an Emergency Use Authorization (EUA).

This is good and will increase the effective number of tests by at least a factor of 2-3 and perhaps more.

In other news, Representative Beyer (D-VA), Representative Gonzalez (R-OH) and Paul Romer have an op-ed calling for more prizes for testing:

Offering a federal prize solves a critical part of that problem: laboratories lack the incentive and the funds for research and development of a rapid diagnostic test that will, in the best-case scenario, be rendered virtually unnecessary in a year.

…We believe in the ability of the American scientific community and economy to respond to the challenge presented by the coronavirus. Congress just has to give them the incentive.

The National Institutes of Health (NIH) have already begun a similar strategy with their $1.4 billion “shark tank,” awarding speedy regulatory approval to five companies that can produce these tests. Expanding the concept to academic labs through a National Institute of Science and Technology (NIST)-sponsored competition has the added benefit ultimately funding more groundbreaking research once the prize money has been awarded.

This is all good but frustrating. I made the case for prizes in Grand Innovation Prizes for Pandemics in March and Tyler and I have been pushing for pooled testing since late March. We were by no means the first to promote these ideas. I am grateful things are happening and relative to normal procedure I know this is fast but in pandemic time it is molasses slow.

Why the FDA is banning the Gates-connected testing kits

Now we know:

An F.D.A. spokesperson said home collection kits raised additional concerns about safety and accuracy that required the agency’s review. The issue in the Seattle case appears to be that the test results are being used not only by researchers for surveillance of the virus in the community but that the results are also being returned to patients to inform them.

The two kinds of testing — surveillance and diagnostic — fall under different F.D.A. standards. In a pure surveillance study, the researchers may keep the results just for themselves. But coronavirus testing has largely revolved around getting results returned to doctors who can share the results with patients.

Here is the full NYT story, via Paul Novosad.  Just stunning.  Here is Alex’s earlier post on the episode.

What is the FDA Doing Now??!

My long-running skepticism about the safety and efficacy of the FDA is fast becoming conventional wisdom. Even normal people can’t believe what they are doing. This piece on the FDA in the New York Times reads like something I might have written for CATO.

An innovative coronavirus testing program in the Seattle area — promoted by the billionaire Bill Gates and local public health officials as a way of conducting wider surveillance on the invisible spread of the virus — has been ordered by the federal government to stop its work pending additional reviews.

…the program, a partnership between research groups and the Seattle and King County public health department that had been operating under authorization from the state, was notified this week that it now needs approval directly from the federal government. Officials with the Food and Drug Administration told the partnership to cease its testing and reporting until the agency grants further approval.

…the Seattle program …has wide backing, including from public health leaders, the Fred Hutchinson Cancer Research Center and Mr. Gates, whose foundation has been deeply involved in fighting the pandemic. The Centers for Disease Control and Prevention also provided an in-person technical adviser to the project.

Dr. Eric Topol, the director of the Scripps Research Translational Institute, who is not involved in the Seattle group, said it had “emerged as leading lights in this whole Covid-19 crisis.” He said it was “bizarre” that the F.D.A. would halt such a project.

By the way, Dr. Helen Chu, one of the leaders of the Seattle project, was one of the first Emergent Ventures prize winners for her work fighting the coronavirus (excellent pick, Tyler!). As you may recall, Chu started testing for coronavirus in an already running flu study without permission. Until she was shut down.

To repurpose the tests for monitoring the coronavirus, they would need the support of state and federal officials. But nearly everywhere Dr. Chu turned, officials repeatedly rejected the idea, interviews and emails show, even as weeks crawled by and outbreaks emerged in countries outside of China, where the infection began.

By Feb. 25, Dr. Chu and her colleagues could not bear to wait any longer. They began performing coronavirus tests, without government approval.

Federal and state officials said the flu study could not be repurposed because it did not have explicit permission from research subjects; the labs were also not certified for clinical work. While acknowledging the ethical questions, Dr. Chu and others argued there should be more flexibility in an emergency during which so many lives could be lost. On Monday night, state regulators told them to stop testing altogether.

The failure to tap into the flu study, detailed here for the first time, was just one in a series of missed chances by the federal government to ensure more widespread testing during the early days of the outbreak, when containment would have been easier. Instead, local officials across the country were left to work in the dark as the crisis grew undetected and exponentially.

History repeats itself, first as tragedy then as farce.

Addendum: I see now that Tyler covered this a bit earlier in the post below. I’ll leave this post up, however, as I have more details including Tyler’s connection.

FDA Prevents Import of Masks

The KN95 mask is China’s version of the N95 mask. 3M, America’s largest manufacturer of N95 masks, said in January that the masks are equivalent. But the FDA is not allowing KN95s into the country.

Buzzfeed: The KN95 mask is a Chinese alternative to the scarce N95 mask, but the FDA refuses to allow it into the country.

…By law, masks, along with most medical devices, can’t be imported or sold in the United States without the Food and Drug Administration’s say-so. Last week, to ease the national shortfall of protective gear, the FDA issued an emergency authorization for non-N95 respirators that had been certified by five foreign countries as well as the European Union. It conspicuously left the KN95 masks out of the emergency authorization.

The omission was all the more startling because in late February the Centers for Disease Control and Prevention said that KN95 masks were one of numerous “suitable alternatives” to N95 masks “when supplies are short.”

…Allowing the importation and use of KN95 could help to greatly alleviate the scarcity.

“The KN95 masks are far more readily available,” said Bob Tilton, who owns a New Jersey–based cosmetics packaging importer and earlier this month decided to use his familiarity with Chinese supply chains to bring in masks and other personal protective equipment to sell to hospitals. “The N95s are much harder to grab.”

Yet without the FDA’s seal of approval, importers are hesitant to order KN95 masks because they worry they’ll get held up at customs.

It’s not just the FDA that is to blame, however. America’s legal system is also to blame:

Many hospitals are refusing to accept them, even as free donations, because they fear legal liability should a health care worker get ill while using a nonpermitted device…Although some hospitals flat-out reject KN95 masks at any price on advice of their lawyers, people rounding up masks to give to hospitals have found that individual doctors or nurses will often accept the donations, given the dire need.

Consider that last bit of insanity. The ethical and common-law type rule is very simple: Do everything reasonable to protect your hospital workers. But what some feckless hospital administrators are actually doing is following “the law” even if it conflicts with the ethical rule.

FDA Stops At-Home Tests

TechCrunch…the U.S. Food and Drug Administration (FDA) has updated its Emergency Use Authorization guidelines to private labs that specifically bar the use of at-home sample collection. This means startups, including Everlywell, Carbon Health and Nurx, will have to immediately discontinue their testing programs in light of the clarified rules.

The FDA issued the updated guidance on March 21, and though some of the companies had already begun to ship their sample collection kits to people, and even begun to receive samples back to their diagnostic laboratory partners, even any samples in-hand will not be tested, and will instead be destroyed in order to comply with the FDA’s request

The tests are collected at home but the tests themselves are done in certified labs under quality-control standards (CLIA). It is of course possible, even likely, that tests collected at home are not as accurate as those collected by a trained nurse. But we don’t want trained nurses to be testing everyone–they have other things to do right now. Furthermore, some of these errors will be detected at the lab and can be fixed with a retest. False negatives are possible but going to a hospital or standing in line to get a test also comes with risk. False negatives will also become apparent to the extent that symptoms worsen at which time patients can seek medical assistance. Yes, of course, delay and false reassurance are also not without risk. Welcome to the world of tradeoffs. But at this point in time we need to unleash American ingenuity and enterprise and evolve our way to the frontier as conditions improve.

We need to learn now, regulate later.

FDA senior scientists

“The White House considered issuing an executive order greatly expanding the use of investigational drugs against the new coronavirus, but met with objections from Food and Drug Administration scientists who warned it could pose unneeded risks to patients, according to a senior government official.

The idea to expand testing of drugs and other medical therapies was strongly opposed by the FDA’s senior scientists this week, the official said, and represented the most notable conflict between the FDA and the White House in recent memory.”

Ahem.  Here is the full WSJ piece.

The FDA and Coronavirus

The failure of the FDA/CDC to adequately prepare for coronavirus, despite weeks of advance notice from China is one of the most shocking and serious examples of government failure that I have seen in my lifetime. After being prevented from doing so, private laboratories are now allowed to offer coronavirus tests and Bill and Melinda Gates’s Foundation is working on an at home swab and test.

But what happens when people get sick? What drugs will patients be allowed to try given that there is no standard treatment available? One experimental antiviral, Remdesivir, was given to the first US patient who was on a downward spiral but seemed to recover after receiving the drug. Gilead, the manufacturer says:

Remdesivir is not yet licensed or approved anywhere globally and has not been demonstrated to be safe or effective for any use. At the request of treating physicians, and with the support of local regulatory agencies, who have weighed the risks and benefits of providing an experimental drug with no data in 2019-nCoV, Gilead has provided remdesivir for use in a small number of patients with 2019-nCoV for emergency treatment in the absence of any approved treatment options.

If Gilead is willing to supply, should patients have a right to try? This seems like a good case for the dual tracking approach proposed by Bartley Madden–let patients try unapproved drugs but collect all information in a public database for analysis. Clinical trials for Remdesivir and other potential drugs are currently underway in China.

Chloroquine, might also be useful against Covid-19. Chloroquine was approved long ago to treat malaria and physicians are allowed to prescribe old drugs for new uses. New uses for old drugs are discovered all the time and they do not have to go through long and costly FDA approval procedures before being prescribed for the new uses. Since chloroquine has never been tested for efficacy against coronovirus, allowing physicians to prescribe it is similar to allowing physicians to prescribe an unapproved drug like Remdesivir. The difference in how new drugs and old drugs for new uses are treated is something of a regulatory anomaly but a fortunate one as I argue in my paper on off-label prescribing.

I suspect that my arguments for less FDA regulation will be relatively well received during the current climate of fear. Bear in mind, however, that for the patient who is dying it’s always an emergency.

Hat tip: Balaji Srinivasan, who really would make a great FDA commissioner.

Why are we letting FDA regulations limit our number of coronavirus tests?

Since CDC and FDA haven’t authorized public health or hospital labs to run the [coronavirus] tests, right now #CDC is the only place that can. So, screening has to be rationed. Our ability to detect secondary spread among people not directly tied to China travel is greatly limited.

That is from Scott Gottlieb, former commissioner of the FDA, and also from Scott:

#FDA and #CDC can allow more labs to run the RT-PCR tests starting with public health agencies. Big medical centers can also be authorized to run tests under EUA. For now they’re not permitted to run the tests, even though many labs can do so reliably 9/9 cdc.gov/coronavirus/20

Here is further information about the obstacles facing the rollout of testing.  And read here from a Harvard professor of epidemiology, and here.  Clicking around and reading I have found this a difficult matter to get to the bottom of.  Nonetheless no one disputes that America is not conducting many tests, and is not in a good position to scale up those tests rapidly, and some of those obstacles are regulatory.  Why oh why are we messing around with this one?

For the pointer I thank Ada.

FDA Dual Track Legislation Advances

S&P Global: Four Republican lawmakers have authored new legislation to permit drugs for critically ill patients to enter the market before completing late-stage trials, saying the bill was necessary because the U.S. Food and Drug Administration’s regulatory process was too slow and burdensome.

The bill would create a time-limited conditional approval pathway in the U.S. similar to a system that has long been used by European regulators.

…The conditional approval would be valid for one year and could be renewed annually for up to five years….Companies would be required to meet certain obligations, like completing clinical investigations to provide full demonstration of safety and effectiveness and other studies.

…Companies could seek full U.S. approval at any time. The FDA would be required to let manufacturers include in their applications the real-world evidence they collected during the conditional approval period.

The lawmakers want the FDA to be able to grant the limited marketing authorization to new drugs that have successfully completed phase 1 and 2 trials, with the idea that companies could generate revenue to help fund their phase 3 studies.

They emphasized their legislation is targeted especially at small biopharmaceutical companies that may struggle to cover the costs of late-stage trials.

Under the dual-track approval system, companies would be able to sell pharmaceuticals earlier but would be required to track outcomes so greater real world information would be developed in the FDA process. The result is a more dynamic approval process better suited to modern medicine. The idea is due to the excellent Bartley J. Madden (note my bias).

Madden and Nobel-prize winner Vernon Smith explained the dual-track idea, noting:

Today’s world of accelerating medical advancements is ushering in an age of personalized medicine in which patients’ unique genetic makeup and biomarkers will increasingly lead to customized therapies in which samples are inherently small. This calls for a fast-learning, adaptable FTCM environment for generating new data. In sharp contrast, the status quo FDA environment provides a yes/no approval decision based on statistical tests for an average patient, i.e., a one-size-fits-all drug approval process.

A similar process has been adopted in Japan for regenerative medicine.

FDA Tiered Approval

have an interesting op-ed on a tiered approval regime for the FDA:

Instituting a codified approval paradigm based on four tiered levels of clinical effectiveness (biomarkers, clinical signs and symptoms, disease modification and clinical outcomes) — with evidence regarding clinical utility progressively increasing — would greatly reduce the regulatory uncertainty and subjectivity, as well as the time to approval of innovative medicines.

Moreover, the four tiers, coupled with a commitment to apply state-of-the-art technologies (Apple Watch, telemetry and other health monitoring systems) to obtain clinical evidence would allow for additional learnings from use of drugs by practicing doctors treating real world patients. This knowledge would unearth additional uses, information that can be added to the product label to allow safer and more effective use of drugs and the identification of drug combinations that lead to even greater health benefits.

See also Bartley Madden’s work on Free to Choose Medicine which would similarly create dual tracks, one the standard FDA process and a second observational track that would bring drugs to market more quickly with the tradeoff being fewer clinical trials. As clinical trials rise in expense and more treatments are targeted towards smaller patients groups (i.e. personalized medicine) and as statistical techniques improve, we will need and can benefit from reforms to the FDA process along these lines.

Bring Back the FDA’s Parallel Track

In 1992, the AIDS/HIV “parallel track” was approved as a regulatory change for FDA to allow patients exclusive access to AIDS/HIV drugs that had passed safety tests but had not yet passed all efficacy tests. Other drugs did not have access to this approval option. As a result of parallel track, the highly effective anti-viral drug stavudine was approved, saving thousands of lives.

…In the years that followed, FDA and Congress created several paths to speed approval and open access to promising medications, including accelerated approval, priority review, fast track, breakthrough therapy, right to try, and expanded access, or “compassionate use.” Unfortunately, these approaches are often confusing, and it is difficult for drug developers to determine which approach to pursue. None of these reforms have matched the openness and simplicity of the parallel track…

Ed Hudgins in How Extending the AIDS Drug Access Model to Other Diseases Would Save Lives.

What is Skim Milk? The FDA versus Dairy Farmers

FDA food regulation isn’t as high stakes as FDA drug regulation but it can be both costly and absurd. A case in point. The FDA controls how foods are labeled with the goal of ensuring that they are “properly” labelled. It’s important that consumers not be misled but what does one say, for example, about soy milk? Is that label proper? (The FDA so far has declined to rule on that issue but the “Defending Against Imitations and Replacements of Yogurt, Milk, and Cheese To Promote Regular Intake of Dairy Everyday Act (DAIRY PRIDE) act may force their hand.)

The FDA’s control over labeling is more powerful than it appears because it can be used to define what a product is. The FDA, for example, can’t force milk producers to add vitamins to milk but by defining milk as including certain vitamins they can say that milk without these vitamins is mislabeled! This is exactly the case with dairy farmer Randy Sowers and South Mountain Creamery. South Mountain Creamery sells skim milk, i.e. milk with the fat skimmed off. The FDA, however, wants skim milk to contain as many vitamins as whole milk so they define skim milk as including vitamin A and D. If farmers want to sell skim milk and call it “skim milk” they have to add vitamins. To avoid prosecution the FDA is requiring South Mountain Creamery to label their skim milk, “imitation skim milk”! Yes. War is Peace. Freedom is Slavery. Real Skim Milk is Imitation Skim Milk. Sowers and the Institute for Justice are suing on First Amendment Grounds.

The FDA has a history of losing First Amendment cases and will probably lose this case as well. A Federal appeals court in Florida has already ruled in a very similar case that labeling skim milk, “skim milk” is not deceptive.

How FDA-Approved Prescribing Information Lags Behind Real-World Clinical Practice

Once a drug has been approved for some use it can be legally prescribed for any use. New uses for old drugs are often discovered. When physicians learn of these new uses, prescribing practices move beyond the uses that the FDA has evaluated and permitted. In Outdated Prescription Drug Labeling, Shea et al. compare off-label uses for cancer drugs that are graded as “well-accepted” by the National Comprehensive Cancer Drugs & Biologics Compendium (NCCN) with the labelled, “FDA-approved” uses. What they find is that most drugs have multiple off-label uses that are significantly different from FDA approved uses.

Our analysis of the NCCN Compendium and FDA drug labels for 43 cancer drugs approved between 1999 and 2011 identified hundreds of off-label uses, most of which were strongly supported by NCCN expert panels.

…Additionally, of the 253 off-label uses, 165 (65.2%) were categorized as “new indications,” meaning they were in disease settings not represented on labels

In my work on off-label prescribing (and with Klein) I have emphasized that the off-label world offers a window on what the larger world would look like with much less FDA control over new drug approvals. Notice that even today it’s physicians and the private approval process, as represented by the compendia, that determine actual prescribing and payment.

We found that 4 of the 5 largest private payers, as well as Medicare, cover over 90% of uses listed on the NCCN Compendium (uses graded 1 and 2A), suggesting widespread acceptance of these uses by diverse stakeholders. While standards for FDA approval differ from standards for coverage determinations, these findings indicate that the gulf between labeled uses and covered uses may be needlessly wide.

To bring FDA labeling up to real-world practice the authors recommend “a collaboration between the FDA and the developers of clinical guidelines and drug compendia to evaluate existing evidence about approved drugs and suggest updates to labeling.” In other words, the decentralized, private approval system should be used to determine which new uses of old drugs are safe and effective and those determinations should then be adopted by the FDA. I agree. But if private practices can be used to approve new uses for old drugs, why shouldn’t similar procedures be used to approve new uses for new drugs?

Cancer, Herpes, Metformin and the FDA

Three articles on medical breakthroughs, or not, caught my eye. The Wall Street Journal discusses a breakthrough in cancer therapy using HIV to target cancer cells. The news is mostly good but the lead researcher worries that it was only luck which prevented the FDA from ending the research prematurely:

Cytokine-release syndrome almost ended the therapy in its infancy. In 2012, Dr. June’s first pediatric patient, 6-year-old Emma Whitehead, developed a 106-degree fever and experienced multiple organ failure. “We thought she was going to die,” he recalls.

A blood analysis showed high levels of the cytokine interleukin-6, or IL-6. “I happened to know because of my daughter’s arthritis that there was a drug that could target IL-6—that had never been used in oncology,” Dr. June recalls. Fortunately, the children’s hospital where Emma was being treated had the medication, Tocilizumab, on hand. “We wouldn’t have had it at the adult hospital because it wasn’t approved at that point for adult conditions.”

Within hours of receiving the drug, Emma awoke from her coma. “It was literally one of those Lazarus conditions,” Dr. June says. Eight days after receiving the CAR T-Cell injection, she went into remission. Two weeks later, she was cancer-free. She’s now 12 and thriving.

Tocilizumab “saved the field” as well as the girl, Dr. June says. “If the first patient dies on a protocol and nobody’s been cured, you’re over.” Regulators, he adds, always “err on the side of caution.” That irks him, since most of his patients would die without the experimental treatments: “Our FDA regulations are made so that you can never have more than about 30% of people get sick with serious side effects. I think we don’t have enough leeway for side effects when you have a potentially curative therapy.”

In my TED talk I argued that the richer China and India are the better it will be for US cancer patients because the bigger the market the greater the incentive to research and develop new drugs. US patients may also get a second benefit. China is big enough to move world R&D which previously was true only for the US and to a lesser extent (because of price controls) the EU. Since the US has by far the largest pharmaceutical market the FDA is a regulatory hegemon. With China we may get to see for the first time a serious alternative to the FDA. And according to some observers, China’s approval process is less-risk averse.

Some of those [new trials] are in the U.S., but more are taking place in China. “There’s a lot more people there, so you can do a lot more trials,” Dr. June says. “But they also put more of their GDP into medical therapy, particularly CAR T-cells.” Beijing’s drug-approval process is easier, too.

I don’t know whether that is true, but it’s a hopeful sign.

In another story, Lawrence Reed has the inspiring story of Bill Halford who has developed a not-yet-approved vaccine for Herpes. Herpes can be incredibly painful and it infects over one million people a year but the route to a vaccine has not been easy:

Impatient with Washington, Halford injected himself, his family and a group of ten herpes patients. None of his family exhibited any ill effects, evidence that the vaccines were safe. All the sufferers enjoyed dramatic pain relief, suggesting effectiveness. The early success of his research led him to co-found, along with film-maker and entrepreneur Agustin Fernandez, a company known as Rational Vaccines, Inc. (RVx)). Its mission is to fight the herpes epidemic worldwide, using the live, attenuated strains that Halford created.

Peter Thiel is a lead investor in Rational Vaccines. Sadly, Bill Halford contracted cancer and died this year at just age 48. I hope his company will carry the ball over the goal line.

Should we all be taking Metformin? Metformin is a diabetes drug but researchers have found that the people taking the drug also get dramatically fewer cancers. Here is Wired:

What they discovered was striking: The metformin-takers tended to be healthier in all sorts of ways. They lived longer and had fewer cardiovascular events, and in at least some studies they were less likely to suffer from dementia and Alzheimer’s. Most surprising of all, they seemed to get cancer far less frequently—as much as 25 to 40 percent less than diabetics taking two other popular medications. When they did get cancer, they tended to outlive diabetics with cancer who were taking other medications.

As Lewis Cantley, the director of the Cancer Center at Weill Cornell Medicine, once put it, “Metformin may have already saved more people from cancer deaths than any drug in history.” Nobel laureate James Watson (of DNA-structure fame), who takes metformin off-label for cancer prevention, once suggested that the drug appeared to be “our only real clue into the business” of fighting the disease.

It’s not just Wired. Here is the title of a recent meta-analysis:

Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.

Metformin is already approved so it could quickly be used off-label  but there is a big problem with anti-aging drugs–there is currently no way any anti-aging drug can get approved.

The assembled scientists and academics focused on one obstacle above all: the Food and Drug Administration. The agency does not recognize aging as a medical condition, meaning a drug cannot be approved to treat it. And even if the FDA were to acknowledge that aging is a condition worthy of targeting, there would still be the question of how to demonstrate that aging had, in fact, been slowed—a particularly difficult question considering that there are no universally agreed-on markers.

The FDA should provide a path to approve anti-aging drugs but if not maybe the CFDA will.